Sulphamoylphenyl pyrrolidinones

ABSTRACT

NEW ANTIEPILEPTIC COMPOUNDS SHOWING EFFECTIVENESS AGAINST BOTH GRAND MAL AND PETIT MAL FORMS OF EPILEPSY COUPLED WITH VERY LOW TOXICITIES AND GOOD IN VIVO STABILITY HAVE THE 1-(SULPHAMOYLARYL)-PYRROLIDIN--2-ONE STRUCTURE; THE PYRROLIDINE RING CARRYING AS POSSIBLE SUBSTITUENTS ALIPHATIC, CYCLOALIPHATIC, CYCLOALKYLIDENE ARALIPHATIC AND ARYL GROUPS; THE SULPHAMOYLARYL PORTION CARRYING AS POSSIBLE SUBSTITUENTS HALOGEN ATOMS OR ALIPHATIC HYDROCARBON, TRIFLUOROMETHYL, ETHER, HYDROXY OR ACYLAMINO GROUPS. THE COMPOUNDS ARE PREPARED BY REACTION OF A SULPHAMOYLARYLAMIDE WITH A BUTYROLACTONE OR Y-HALOBUTYRYL HALIDE OR BY HALOSULPHONATION BY A CORRESPONDING 1-ARYLPYRROLIDIN-2ONE AND REACTION WITH AMMONIA OR AN AMINE.

United States Patent Office 3,813,387 SULPHAMOYLPHENYL PYRROLIDINONESRolf Wilheim Pfirrmann, Lucerne, and Emil Hofstetter,

Wolhusen, Switzerland, assignors to Ed. Geistlich Sohne A.G. furChemische Industn'e No Drawing. Filed Aug. 4, 1971, Ser. No. 169,062Claims priority, application Grgaat Britain, Aug. 5, 1970,

9 Int. Cl. C07d 27/08 US. Cl. 260-2396 10 Claims ABSTRACT OF THEDISCLOSURE This invention relates to novel compounds of use in thetreatment of epilepsy and to processes for their preparation.

In general, the majority of the available antiepileptic drugs are activeagainst either grand mal or petit mal epilepsy but not against bothforms. We have now found that novel sulphamoylphenyl pyrrolidinones haveshown good activity in both the electroshock and cardiazoleshock tests,indicative of activity against both grand and petit mal forms ofepilepsy.

According to the present invention we provide compounds of the generalformula R C-ii! /NR 11 -c1u R R I where R R R R, R and R which may bethe same or different are hydrogen atoms, aliphatic groups,cycloaliphatic groups, araliphatic groups or aryl groups or R and R Rand R or R and R may together represent a cycloalkylidene group; and Ris an aryl group carrying at least one sulphamoyl group and their saltswith bases.

R is preferably a sulphamoylphenyl group which may, for example, havethe formula SOzNR R where R represents one or more hydrogen or halogenatoms, or aliphatic hydrocarbon, trifiuoromethyl ether, hydroxy oracylamino groups; and R and R which may be the same or different, arehydrogen atoms, heterocyclic groups, such as pyridyl, pyrimidyl orimidazolyl groups, or aliphatic hydrocarbon groups which may, ifdesired, carry substituents such as oxo, hydroxyl, carboxyl oresterified carboxyl, or amino or alkylamino groups, or together with thenitrogen atom to which they are attached, form a heterocyclic group,e.g. a piperidyl or piperazyl group; and their salts with bases.

Patented May 28, 1974 R is preferably a halogen atom such as bromine, ormore preferably fluorine or most advantageously chlorine. Compounds inwhich the sulphamoyl group SO NR R is in the 4-position are especiallypreferred for their good anti-convulsant activity, especially those inwhich R is a chlorine or fluorine atom.

R and R may, for example, be alkyl groups having 1-5 carbon atoms, i.e.methyl, ethyl, propyl, butyl or amyl groups, acyl groups such as acetylor benzoyl groups, alkoxy carbonyl groups such as ethoxy carbonylgroups, carbamyl groups e.g. the n-butylaminocarbonyl group,hydroxyalkyl groups, e.g. ,B-hydroxyethyl, or estcri-fied carboxyalkylgroups e.g. ethoxycarbonylethyl groups. The preferred compounds,however, are those in which R and R are both hydrogen.

Where any of R R R R R and R are aliphatic groups they are preferablyalkyl or alkenyl groups, advantageously having 1-8 carbon atoms, mostpreferably 1-5 carbon atoms, for example, methyl, ethyl, propyl, butyl,amyl, hexyl, heptyl or allyl groups which may carry substituents such asaryl groups, for example phenyl groups, which may be substituted asdescribed below. Such groups may thus include benzyl, phenethyl andphenylallyl groups. One or more of R R R R R and R may be acycloaliphatic group, for example a cycloalkyl or cycloalkenyl, or twoadjacent groups, i.e. R and R R and R or R and R may constitute togethera cycloalkylidene group such as a cyclopentylidene or cyclohexylidenegroup. Cycloalkyl groups may, for example, include cyclopentyl andcyclohexyl groups which cycloalkenyl groups may, for example, includecyclopentenyl and cyclohexenyl groups in which the double bond is in anyof the available positions. Such groups in general preferably contain3-8 carbon atoms, advantageously 4-7 carbon atoms.

Where one or more of R R R R R and R is aryl, or araliphatic, this maycarry one or more alkoxy, methylene dioxy, nitro, cyano, acyl, carboxyl,esterified carboxyl, amino, alkylamino, sulphonamide or acylamido groupsor halogen atoms. The phenyl or chlorophenyl group is preferred.

One pair of substituents R and R or R and R or R and R mayadvantageously be methyl groups or alternatively one of the substituentsmay advantageously be a phenyl group, while the remainder are preferablyall hydrogen atoms. R is also advantageously a methyl group While R is aphenyl group and the remainder are hydrogen atoms.

The new compounds form salts with bases, for example alkali metal saltse.g. sodium salts or salts with ammonia or amines.

As mentioned above, the compounds according to the present inventionshow interesting activity against both grand mal and petit mal forms ofepilepsy. This activity is indicated respectively by the electro shocktest and the Cardiazol shook test. Activity and toxicity for twoparticularly noteworthy compounds as compared with the available druga-ethyl-a-methylsuccinimide (C) are shown in the following table. Thecompounds are A, l-(p Sulphamoylphenyl)4-methyl-4-phenylpyrrolidin-2-one and B, 1-(2chloro-4-sulphamoylphenyl)-4-phenylpyrrolidin- 2-one, the products ofExamples 15 and 17 respectively.

It will also be noted that the ratio of ED /LD is significantly betterfor the compounds according to the invention.

The compound showed no sedative activity up to 500 mg./kg., andfurthermore showed a better stability in viva than available succinimideanti-epileptic drugs.

()ther compounds according to the invention have similar properties; theparticularly preferred products include:

l-(p-sulphamoylphenyl -3,3-dimethyl-pyrrolidin-Z-one,

1- (p-sulphamoylphe nyl -4,4-dimethyl-pyrrolidin-2-one,

l- (psulphamoylphenyl) -5,S-dimethyl-pyrrolidin-Z-one,

l- (p-sulphamoylphenyl) -4,4,S-trimethyl-pyrrolidin-2-one,

1- (p-sulphamoylphenyl -3,3,S-trimethyl-pyrrolidin-2-one,

1- (p-sulphamoylphenyl) -4-methyl-4-ethyl-pyrrolidin-Z- one,

1- (psulphamoy1phenyl) -3 -phenyl-pyrrolidin-Z-one,

l (2-chloro-4-sulphamoylphenyl) -3-phenyl-pyrrolidin-2- one,

1- p-sulphamoylphenyl) -4-phenyl-pyrrolidin-2-one, and

l- (p-sulphamoylphenyl) -S-phenyl-pyrrolidin-Z-one.

According to a further feature of the invention we pro- 'videpharmaceutical compositions containing one or more compounds accordingto the invention together with one or more pharmaceutical carriers orexcipients.

Thus, for example, the compositions may take the form of tablets, coatedtablets, capsules, lozenges, suppositories, ampoules for injection,solutions, etc.

The carriers or excipients in such compositions may, for example bethose conventional for such forms and may include starch, lactose,magnesium stearate, talc, gelatin, sterile pyrogen-free water, orsuspending, emulsifying, dispersing, thickening or flavouring agents.

Dosage units forms such as tablets, capsules, suppositories or ampoulesare preferred and advantageously each unit contains to 1000 mg. ofactive substances, preferably 100 to 300 mg.

The compositions, preferably contain the active substance at aconcentration from 0.10 to 80.0% by weight.

According to a still further feature of the invention we provide aprocess for the preparation of compounds of the general formula I asdefined above wherein a compound of the general formula RNH preferably acompound of the formula:

smNR R' II (where R', R and R are as defined above) is reacted with abutyrolactone of the general formula (where R R R R, R and R are asdefined for formula I above) at an elevated temperature in the presenceof a dehydration catalyst such as zinc chloride or aluminum chloride.The reaction is conveniently effected in the absence of a solvent atelevated temperature e.g. in an autoclave at a temperature of from 150to 300 C. e.g. about 240 C.

According to an alternative process according to the present invention,the compound RNH is reacted with a butyric acid derivative of thegeneral formula:

(where R R R R, R and R are as defined above 'and X is a halogen atompreferably bromine). The reaction is preferably efiected in a cyclicether solvent such as dioxan or tetrahydrofuran, advantageously at anelevated temperature, e.g. from 75 to 150 C., for example about 100 C.

The reaction with the compound of formula IV may be effected in a singlestage, or in two stages. In the latter case the product of the firststage, which is accomplished simply by heating, will have the generalformula:

RI IU-(l-OO \NHR -CX is 1% R v (where R R R R R and R and X are asdefined above) and the final condensation proceeds by ring: closure ofthis compound by elimination of HX preferably in the presence of a base,for example an alkali metal amide or hydride e.g. sodamide, in a cyclicether solvent such as dioxan or tetrahydrofuran. The intermediate V ispreferably isolated from the initial starting materials and the productof formula I before being cyclized.

The dihalogeno compound of the formula IV may be prepared by thereaction of a lactone of the formula III with a halogenating agent, e.g.a phosphorus pentahalide such as phosphorus pentabromide or phosphoruspentachloride, conveniently at an elevated temperature, for example75l50 C. e.g. 90l00 C.

The pyrrolidinone compounds according to the invention may also beprepared from corresponding compounds lacking a sulphamoyl group byreaction with reagents for introducing a sulphamoyl group. Thus, forexample, a compound of formula it the (where R R R R R R and R are asdefined above and Hal is a halogen atom, e.g. chlorine) may be reactedwith ammonia or an amine of the formula NH-R R where R and R have theabove meanings. The group SO Hal can be introduced by reaction of acompound of the formula o n R I R VIII (where R R R R R R and R are asdefined for formula I) and treatment with sulphur dioxide in thepresence of a cuprous halide. The amine of formula VIII can be preparedby reduction of the corresponding nitro compound, which nitro compoundmay be prepared by reacting a nitroaniline with a compound of formulaIII or IV in a process analogous to that described earlier, or bynitration of a compound of formula VII. It will be understood that in asulphonation or nitration reaction any other aryl groups present in themolecule, e.g. on the pyrrolidinone ring, can also be sulphonated ornitrated.

The compounds of formula I in which one or both of R and R are hydrogencan be used to prepare derivatives thereof. Thus, for example, acylationgives the acyl derivatives, e.g. by reaction with an acyl halide oranhydride; alkylation gives the alkyl derivatives, e.g. by reaction withan alkyl halide, sulphate, sulphonate, etc. Hydroxyalkylation gives thehydroxyalkyl derivative, e.g. by reaction with ethylene oxide;carbamylation gives the corresponding urethane, e.g. by reaction with acarbonyl dihalide followed by reaction with ammonia or an amine.Urethane derivatives can be prepared, for example, byreaction with ahaloformic acid ester, e.g. a chloroformic acid ester, preferably analkyl ester having 1-5 carbon atoms in the alkyl group. Saturatedsubstituents R R R R R or R can be prepared from correspondingunsaturated substituents and thus, for example, an n-propyl substituentcan be prepared from an ally] substituent or a cycloalkyl substituentfrom a cycloalkenyl substituent by reduction, e.g. catalytichydrogenation, for example, using a platinum catalyst.

In order that the invention may be well understood we give the followingexamples by way of illustration only (all temperatures are in C.).

The starting materials used in the examples may be prepared by themethods disclosed in the following publications:

Example Literature 4 J. Chem. Soc. 1949, 2745. 8+11 J. Am. Soc. 73, 448(1951). 12 I. Am. Soc. 69, 11 (1947). 12 Blst. 17, 319.

EXAMPLE 1 1- (p-sulphamoylphenyl )-pyrrolidin-2-one1-phenylpyrrolidin-2-one (3 g.) was mixed 'with chlorosulphonic acid (20ml.) and the mixture was heated at 140160 during 20 minutes. The mixturewas then poured into ice and the precipitated acid chloride was washed,dissolved in chloroform (50 ml.) and treated with concentrated ammonia(50 ml.). The reaction mixture was heated under reflux for 15 minutesand then cooled. The precipitated material was filtered ofi? undersuction and dried, to yield 3.5 g. M.P. 236238 C. The product wasrecrystallized from DMF-ether to M.P. 240- 214 C.

Found: C, 50.23; H, 5.01; N, 11.53; CH12N2O3S Requires: C, 50.00; H,5.03; N, 11.66%

EXAMPLE 2 1-( p-sulphamoylphenyl)-3,3-dimethylpyrrolidin-Z-one1-phenyl-3,3-dimethylpyrrolidon-2-one (2.8 g.) was reacted withchlorosulphonic acid and the product treated with ammonia in a manneranalogous to that of Example 1 to give a crude yield of 1.1 g.Recrystallization from ethyl acetate gave M.P. 210-211 C.

Found: C, 53.52; H, 5.96; N, 10.39; S, 11.98 C H N O S (268.26)

Requires: C, 53.72; H, 6.01; N, 10.44; S, 11.92%

EXAMPLE 3 l-(p-sulphamoylphenyl)-4,4-dimethylpyrrolidin-2-one l-phenyl4,4 dimethylpyrrolidin 2 one (6 g.) was treated analogously to themethod of Example 1 to yield the p-sulfamoyl derivative (4.8 g.) M.P.191193 C. (from ethylacetate).

Found: C, 53.78; H, 6.04; N, 10.42; S, 11.83 C12H16N2O3S Requires: C,53.72; H, 6.01; N, 10.44; S, 11.92%.

EXAMPLE 4 1-(p-sulphamoylphenyl)-4,4-dimethyl pyrrolidin-Z-one3,3-dimethylbutyrolactone (6 g.) zinc chloride (dry) (0.2 g.) andsulfanilamide (9.1 g.) were heated together 6 in an autoclave for 24hours at 220-240 C. The black reaction mixture was thoroughly extractedfirst with dilute hydrochloric acid and then with hot ethylacetate. Theeth ylacetate solution was diluted with petroleum ether to yield aprecipitate of the title compound (1.5 g.) which was recrystallized fromethylacetate to M.P. 19l-193 C. This compound is identical with theproduct of Example 3.

EXAMPLE 5 1- (p-sulphamoylphenyl) -5 ,5 -dimethyl-pyrrolidin-2- one By amethod analogous to that of Example 1, 1-phenyl-S,S-dimethylpyrrolidin-Z-one (3 g.) yield a crude product (1.6g.) which on recrystallization from ethylacetate or alcohol gave thepure product, M.P. 203- 204 C.

Found: C, 53.71; H, 5.99; N, 10.35; S, 11.88 C H N O S (268.26)Requires: C, 53.72; H, 6.01; N, 10.44; S, 11.92%

EXAMPLE 6 l-(p-sulphamoylphenyl) 4,4,5 trimethyl pyrrolidin-2- one (I)and l-(p-sulphamoylphenyl)-3,3,5-trimethylpyrrolidin-Z-one (II) Amixture of 1-phenyl-4,4,5-trimethyland l-phenyl-3,3,5-trimethyl-pyrrolidin-Z-one (9 g.) was treated by a methodanalogous to that of Example 1 to yield a crude product (6.3 g.) whichon recrystallization from ethylacetate yielded I (crude) (4.8 g.), themother liquors containing II (crude) (ca. 1 g.) I was recrystallizedfrom ethylacetate to M.P. 153-154 C.

Found: C, 55.30; H, 6.37; N, 9.92; S, 11.24 C H N O S (282.29) Requires:C, 55.31; H, 6.43; N, 9.92; S, 11.32%

NMR: CH not coupled with CH, therefore I. II was recrystallized fromethylacetate to M.P. 175 177 C.

Found: C, 55.20; H, 6.32; N, 9.80; S, 11.32 C H N O S (282.29) Requires:C, 55.31; H, 6.43; N, 9.92; S, 11.32%

NMR: CH coupled with CH, therefore II.

EXAMPLE 7 1-(p-sulphamoylphenyl)-4-methyl-4-ethylpyrrolidin- 2-one 1phenyl 4-methyl-ethyl-pyrrolidin-2-one was reacted with chlorosulphonicacid and then with ammonia by the method of Example 1 to yield a crudeproduct (6.3 g.) recrystallized from acetone-ethyl-acetate-petroleumether to M.P. 184-186" C.

Recrystallization from ethylacetate gave M.P. 198- 199 C.

Found: C, 60.76; H, 5.14; N, 8.81; S, 10.10. C H N O (316.30) Requires:C, 60.75; H, 5.10; N, 8.86; S, 10.11%

EXAMPLE 9 1- (p-sulphamoylphenyl -3-pheny1-pyrrolidin-2-one 2phenylbutyrolactone (17 g.) was heated with phosphorus pentabromide (70g.) one hour at -100" C. and the mixture allowed to stand overnight at2025 C. The

dark solution was distilled at 102-133 C. (0.2 nm. Hg) to yield theintermediate 2-phenyl-4-bromobutyryl bromide (28.7 g.) This intermediatewas dissolved in absolute dioxan (50 ml.) and added to a solution. ofsulfanilamide (32.4 g.) in absolute dioxan (200 ml.). The reactionmixture was heated at 90-l00 C. for one hour and the precipitatedsulfauilamide hydrobromide was filtered 01f. The filtrate was thenevaporated to dryness in vacuo and the residue (34 g.) was washed withwarm ether to yield a residue (24 g.) of crude 2-phenyl-4-brornobutyrosulfanilamide.

The ether solution was concentrated and the residue dissolved in dilutesodium hydroxide. Addition of dilute hydrochloric acid precipitated thedesired product (5.6 g.).

The 2 phenyl 4-bromobutyro-sulfanilamide (24 g.) was dissolved inabsolute dioxan (250 ml.) and powdered sodamide (4 g.) added. Thereaction mixture was heated under reflux for two hours and theprecipitated matter filtered oil from the dioxan solution under suction.The filtrate was evaporated to dryness in vacuo and the residue treatedwith dilute sodium hydroxide (200 ml.) to give a precipitate. Thesuspension was then acidified with dilute hydrochloric acid and theresulting precipitate filtered oil under suction and dried to give acrude yield of 8.3 g. (plus 5.6 g.), M.P. l70176 C. Recrystallizationfrom alcohol gave M.P. 197-199' C. The product is identical with that ofExample 8.

EXAMPLE 1- p-sulphamoylphenyl) -4-methyl-4-phenyl-pyrrolidin- 2-one3-methyl-3-phenylbutyrolactone (24 -g.), zinc chloride (1 g.) andsultanilamide (24 g.) were heated in an autoclave at 230-250 C. for 13hours in a method analogous to that of Example 4. The reaction mixturewas triturated with dilute hydrochloric acid and the insoluble portionwas separated and boiled with ethylacetate (800 ml.). The ethylacetatesolution was filtered over active charcoal and evaporated to dryness.The residue was washed with warm ether to leave a residue (10 g.). Thisresidue was chromatographed on silica gel with chloroform andchloroform-methanol to give product (3.1 g. crude). Recrystallizationfrom ethyl-acetate gave M.P. 171- 172 C.

Found: C, 61.71; H, 5.55; N, 8.40; S, 9.78 C H N O S (330.33) Requires:C, 61.81; H, 5.49; N, 8.48; S, 9.68%

EXAMPLE 11 1-(2-chloro4-sulphamoylphenyl)-3-phenyl-pyrrolidin- 2-oneUsing the method described in Example 9, Z-phenylbutyrolactone (17 g.)was treated with phosphorus pentabromide (70 g.) to yield the bromide(28.2 g.). This intermediate was dissolved in dioxan and reacted with 3-chloro-4-aminobenzenesulphonamide (38.4 g.) according to the method ofExample 9. The crude product (11.5 g.) was obtained from the ethersolution and 2-phenyl-4- bromo N(2-chloro-4-sulphamoylphenyl)-butyramide (26 g.), insoluble in ether,was also obtained. This byproduct was reacted with sodamide (5 g.) indioxan as before to yield after treatment with water and hydrochloricacid further crude product (12.4 g.). Multiple recrystallization fromcopious ethyl acetate gave M.P. 211213 C.

Found: C, 54.67; H, 4.30; N, 8.07; S, 9.25; Cl, 10.0 C H ClN o S (350.8)Requires: C, 54.75; H, 4.31; N, 7.98; S, 9.14; Cl, 10.1%.

EXAMPLE 12 l-(p-sulphamoylphenyl)-4-phenyl-pyrrolidin-Z-one IPreparation analogous to Example 9.

8 g. of 3-phenylbutyrolactone were brominated with 35 g. of phosphoruspentabromide. The resulting 3-phenyl-4- bromobutyrobromide (14.3 g.,B.P. 0.3 mm., 125 to 131 C.) was reacted in dioxan with 16.2 g. ofsulphanilamide. Without isolating the3-phenyl-4-bromo-N-(p-sulphamoylphenyU-butyramide, the dioxan solutionwas mixed with 6 g. of sodamide.

The crude product (dioxan residue) was dissolved and reprecipitated(NaOH/HCl), filtered over silica gel in chloroform/acetone (7:3) andrepeatedly recrystallized from alcohol. 2.1 g. of pyrrolidone wasobtained, M.P. 198 to 204 C. (sintering at 186 C.)

For elementary analysis, a sample was recrystallized from ethyl acetateand alcohol; M.P. 202 to 204 C.

C H N O 'S (316.30).Calc.: C, 60.67; H, 5.10; N,

8.86%. Found: C, 60.79; H, 5.16; N, 8.92%.

EXAMPLE 13 Mixture of 1-phenyy-3-cyclohexyl-pyrrolidin-2-one andl-phenyl-4-cyclohexyl-2-pyrrolidin-2-one 2 g. of a mixture of2-cyclohexylbutyrolactone and 3- cyclohexylbutyrolactone (about 1:1according to g.l.c.) were kept with 4.65 g. of aniline and 2.6 g. ofaniline hydrochloride is a sealed vessel for 4 hours at 230 to 240 C.(oil bath). The reaction mixture was then taken up in chloroform/ether,washed with dilute hydrochloric acid and water, dried over sodiumsulphate and freed from solvent again by evaporation.

3.5 g. of the residual oil were dissolved in ether/hexane and 2.5 g. ofthe pyrrolidone, M.P. to 119 C. (sintering from 73 C.) crystallized. Asample was recrystallized from hexane; M.P. 113 C. (sintering from 73C.).

C H NO (243.35).Calc: C, 78.96%; H, 8.70; N, 5.7%.

Found: C, 78.90; H, 8.70; N, 5.70%.

EXAMPLE 14 Mixture ofl-(p-sulphamoylphenyl)-3-cyclohexyl-pyrrolidin-Z-one and 1(p-sulphamoylphenyl)-4-cyclohexylpyrrolidin-Z-one 5 g. of an isomermixture of 1-phenyl-3- or 4-cyclohexyl-Z-pyrrolidone and 27 ml. ofchlorosulphonic acid were heated for 20 minutes at C. The reactionmixture was then poured onto ice. The water-insoluble part was taken upin chloroform, separated, mixed with 50 ml. of concentrated ammonia andrefluxed for 10 to 15 minutes. After cooling, the crude product wassuction-filtered and dried, yield 4.6 g. Crystallization from ethylacetatehexane gave 4.5 g.; M.P. 180 to 186 C. (sintering from 152 C.).Recrystallization from ethyl acetate gave a sample M.P. 190 to 196 C.(sintering from 158 C.).

C H N O S (322.43).-Calc.: C, 59.63; H, 6.87; N,

8.68%. Found: C, 59.58; H, 6.86; N, 8.59%.

EXAMPLE 1's 1-( 2-chloro-4-sulphamoylphenyl) -4-phenyl-pyrrolidin- 2-oneA solution of 28.2 g. of 3-phenyl-4-bromobutyrobromide (cf. Example 12),38.4 g. of 3-chloro-4-aminobenzenesulfonamide and 450 ml. of dioxan wasrefluxed for an hour. Without isolating the 3-phenyl-4-bromo-N-(2-chloro-4-sulphamoylphenyl)-butyramide, the filtered dioxan solution wasmixed with 7 g. of sodamide and boiled for an hour.

The dark dioxan solution was filtered and evaporated to dryness. Theresidue was dissolved in dilute caustic soda solution and then acidifiedwith hydrochloric acid. The resulting precipitate was suction-filtered,dried (14.6 g.) and dissolved in ethyl acetate. The ethyl acetatesolution was filtered over silica gel and somewhat evaporated.

9 12.1 g. of crude product, M.P. 167 to 170 C. crystallized and wererepeatedly recrystallized from ethyl acetate; M.P. 171 to 173 C.

C H ClN O S (350.80). Calc.: C, 54.75; H, 4.31; N,

7.98%. Found: C, 54.64; H, 4.35; N, 8.05%.

EXAMPLE 16 (a) 3-phenyl-4-bromo-N- ('2-chloro-4-nitrophenyl) butyramide29 g. of 2-chloro-4-n-itroaniline were dissolved in 250 ml. of absoluteether and slowly mixed with a solution of 25.4 g. of3-phenyl-4=bromobutyrobromide (cf. Example 12) and 50 ml. of absoluteether. A yellow'precipitate was obtained. After 2 hours the refluxedmixture was cooled and suction filtered (precipitate:2-chloro-4-nitroaniline-hydrobromide) The ether filtrate was evaporatedto 50 and cooled to C. 18.1 g. of crude product, M.P. 120 to 122 C.crystallized. After repeated recrystallization from ethyl acetate thecompound melts at 134 to 136 C.

c H isrciN o, (397.5).Calc.: c, 43.40; H, 3.30;

7.06%. Found: C, 48.52; H, 3.45; N, 7.02%.

(b) 4-phenyl-1-(2-chloro-4-nitropl1enyl) -pyrrolidin-2- one C H ClNO O(316.80.-Ca1c.: C, 60.62; H, 4.13; N,

8.84%. 'Found: C, 60.91; H, 4.20; N, 8.91%.

EXAMPLE 17 1 (2 chloro-4sulphamoylphenyl)-4-phenyl-pyrrolidin- 2 onefrom 1-(2-chloro-4-aminophenyl)-4-phenyl-pyrrolidin-2-one 5.4 g. of4-phenyl-1-(2-chloro-4-uitrophenyl)-pyrrolidone were dissolved in 200ml. of alcohol and hydrogenated with platinum oxide at 20 C. at normalpressure. After the calculated quantity of hydrogen had been taken up,the catalyst was separated :by filtration. The clear filtrate wasevaporated to dryness in vacuo to give 4.8 g. of a glassy brittlesubstance: 1-(2-chloro-4-aminophenyl)- 4-phenyl-pyrrolidin-2-one.

IR-spectrum: 3510, 3420 cm.- (NH free valency vibrations) (in CH Cl3080, 3060, 2990-2900 cm.- (=CH, CH, CH valency) 1697 cmr (C=O,'y-lactam) 1625 cm." (NH- deformation vibrations) 1602, 1510 cm.- (C=C,ring vibrations) 1248 cm.- (CN, primary aromatic amine).

2.7 g. of crude 1-(2-chloro-4aminophenyl)-4-phenyl-pyrrolidin-2-one weredissolved in 10 ml. of glacial acetic acid and 12 ml. of concentratedhydrochloric acid and diazotized at 0 to C. with 0.9 g. of sodiumnitrate dissolved in 4 ml. of water.

The diazonium solution was then added at 0 C. to a solution of 20 ml. ofglacial acetic acid and 0.6 g. of copper (11) chloride which wassaturated with sulphur dioxide. At the end of gas evolution 50 ml. ofwater were added and the corresponding sulphonic acid chloride wasprecipitated. This was dissolved in about 30 ml. of chloroform and mixedwith 40 ml. of concentrated ammonia. The reaction mixture was thenboiled for 15 minutes and evaporated to dryness. The residue wassubjected to chromatography on silica gel made up in chloroform.

From the chloroform-methanol fractions (99:1 and 98:2) 1.8 g. of crudepyrrolidone were obtained. Recrystallized from ethyl acetate, theproduct melts at 171 to 173 C.

From melting point, mixed melting point, IR-Spectrum and thin layerchromatography, the compound is identical to the1-(2-chloro-4-sulphamoylphenyl) 4 phenyl-pyrrolidin-Z-one described inExample 15.

EXAMPLE 18 1- (2-fluoro-4-sulphamoylphenyl -4-phenylpyrrolidin-Z-one32.4 g. of 3-phenyl-4-bromobutyrobromide (cf. Example 12) were dissolvedin 50 ml. of absolute dioxan and added to a solution of 39 g. of3-fiuoro-4-amino-benzenesulfonamide and 500 ml. of dioxan. The reactionmixture was refluxed for an hour and after cooling and standingovernight was filtered. The filtrate (the dioxan solution contains(3-phenyl-4-bromo-N-(2 fluoro 4 sulphamoylphenyl)-butyramide) was mixedwith 8 g. of sodamide and refluxed for 30 minutes. During boiling sodiumbromide was precipitated and was removed by filtration. The dioxan wasdistilled off and the residue was purified by dissolving in caustic sodasolution and by precipitating with concentrated hydrochloric acid togive a crude yield of 11.6 g., M.P. approx. 196 C.

Repeated crystallization from ethyl acetate and acetone (with activatedcharcoal) gave a sample with melting point 222 to 224 C.

C H FN O S (334.3)

Calc.: C, 57.53; H, 4.53; N, 8.39; F, 5.69; S, 9.60% Found: C, 57,47; H,4.47; N, 8.41; F, 5.52; S, 9.48%

EXAMPLE 19 1- (3 -chloro-4-sulphamoylphenyl) -4-phenylpyrrolidin-Z-onePreparation analogous to Example 18 with 2.5 g. of 3-phenyl 4bromobutyrobromide and 1.7 g. of 2-chloro- 4-aminobenzenesulfonamide.The dioxan solution contain ing the non-isolated intermediate3-phenyl-4-bromo-N-(3- chloro-4-sulphamoylphenyl)-butyramide was treatedwith 2.5 g. of sodamide as described in Example 18 to eflectcyclization.

After filtration of the reaction mixture, the dioxan solution wasevaporated to dryness (no residue) and the filter residue was mixed withice/Water and acidified. A precipitate was obtained in the form of 1.1g. of crude product which was subjected to chromatography on silica gelmade up with chloroform.

From the chloroform-methanol (99:1) fraction, 0.2 g. of pyrrolidone wasobtained, M.P. (from ethyl acetate) 200 to 201 C.

C H ClN O S (350.8)

Calc.: C, 54.74; H, 4.31; N, 7.98% Found: C, 54.85; H, 4.36; N, 8.08%

EXAMPLE 20 (a) 4-methyl-1,4-diphenyl-pyrrolidin-Z-one 3.3 g. of 3-methyl3 phenylbutyrolactone, 8.8 g. of aniline and 4.7 g. of anilinehydrochloride were kept together in an autoclave for 4 hours at 180 toC. After cooling, the reaction mixture was mixed with 100 ml. of dilutehydrochloric acid and the separated oil taken up in ether. The etherlayer was separated, dried over sodium sulphate and evaporated. The darkoily residue was distilled to yield 1.5 g. of crude pyrrolidone, B.P.,0.1 mm.,

115 to 118 C. The pyrrolidone was crystallized from ethylacetate/petroleum ether, M.P. 59 to 60 C.

C H NO (251.31)

Calc.: C, 81.24; H, 6.82; N, 5.57% Found: C, 81.20; H, 6.84; N, 5.41%

(b) 4-methyl-1,4-di-(sulphamoylphenyl) pyrrolidin-Z-one 2 g. of4-methyl-l,4-diphenyl-pyrrolidin-2-one and 15 ml. of chlorosulphonicacid were heated together for 30 minutes at 160 C. After cooling; thereaction mixture was poured carefully onto ice. The precipitatedsulphonic acid chloride was separated by filtration and dissolved moist(2.1 g.) in 100 ml. of chloroform. The chloroform solution was stirredwell with 200 ml. of concentrated ammonia for 2 hours at 20 to 25 C. andthen evaporated to dryness in vacuo. The residue (1.8 g.) was dissolvedin dilute caustic soda solution, filtered and precipitated withconcentrated hydrochloric acid. The precipitate was filtered and driedto yield 1.3 g. of crude pyrrolidone, M.P. 140 to 160 C. (sintering from100 C.). The product was purified by filtration over silica gel withchloroform-methanol (4:1), by dissolving and precipitating (NaOH/HCI)and by recrystallizing from water; M.P. 140 to 150 C. (sintering from120 C.).

C H N O S (409.35)

Calc.: C, 49.88; H, 4.68; N, 10.27; S, 15.62% Found: C, 49.53;H, 4.69;N, 10.14; S, 15.67%

EXAMPLE 21 1-(2-su1phamoylphenyl)-4-phenylpyrrolidiu-Z-one Preparationanalogous to that of Example 18 using 28.7 g. 3-phenyl 4 bromobutyrylbromide and 32.4 g. o-sulphanilamide. The dioxan residue was dissolvedin dilute caustic soda, filtered and re-precipitated with nitric acid.The precipitate was dried and extracted with ethyl acetate. The ethylacetate-soluble portion was then chromatographed on silica gel made upwith chloroform. From the chlorofrom-methanol fraction (95:5) 3.0 g.pyrrolidone were obtained M.P. 168-171 C. (from ethyl acetate).

C -H N O S (316.30)

Calc.: C, 60.75; H, 5.10; N, 8.86% Found: C, 60.59; H, 5.12; N, 8.87%

EXAMPLE 22 1- (Z-methyl-4-sulphamoylphenyl) -4-phenylpyrrolidin-2- onePreparation analogous to that used in Example 18, using 17 g.3-phenyl-4-bromobutyryl bromide and 20.5 g. 3-methyl-4-aminobenzenesulphonamide. The dioxan-insoluble part was, as in Example 19, added toice and made strongly alkaline with dilute caustic soda. The mixture wasfiltered and acidified with nitric acid. The precipitate was dissolvedin ethyl acetate filtered, dried and evaporated to yield a residue of 14g. This residue was dissolved in chloroform and chromatographed onsilica gel. From the chloroform-methanol (98:2) fraction 7 g.pyrrolidone were obtained, M.P. 160l65 C. Recrystallization from ethylacetate raises the M.P. to 204- 207 C. (sinters).

12 EXAMPLE 23 1-(2-chloro-4-sulphamoylphenyl)-S-phenylpyrrolidin- 2-0nePreparation analogous to Example 22 from 8 g. 4- phenyl-4-bromobutyrylbromide and 10.9 g. 3-chloro-4- aminobenzene sulphonamide. Theunisolated intermediate was cyelised with 4 g. sodamide. Yield 8.4 g.(crude); M.P. after purification as in Example 22 -l76 C.

We claim:

1. A compound of the formula wherein R R R R, R and R, which may be thesame or different, are hydrogen, n-alkyl or n-alkenyl groups c0ntaining1-5 carbon atoms, cycloalkyl or cycloalkenyl groups of 3-8 carbon atoms,phenylalkyl or phenylalkenyl groups with up to 8 carbon atoms in thealkyl or alkenyl portion, phenyl groups or phenyl groups substituted byhalo or sulphamoyl, or R and R R and R or R and R may together representa cyclo-alkylidene group of 3-8 carbon atoms, provided that at leastthree of R R are hydrogen, and R is hydrogen, a

halogen atom or a methyl group; or an alkali metal ammonia or amine saltthereof.

2. A compound as claimed in claim 1 in which each cycloalkyl,cycloalkenyl or cycloalkylidene group has 4-7 carbon atoms.

3. A compound as claimed in claim 1 in which any of R R R R, R and R isa phenyl group substituted by halo or sulphamoyl.

4. A compound as claimed in claim 1 in which R is a chlorine or fluorineatom.

5. A compound as claimed in claim 1 in which the group SO NH is in the4-position.

6. A compound as claimed in claim 1 in which one pair of substituents Rand R or R and R or R and R are methyl groups; or in which one of thesubstituents R R R R R and R is a phenyl group and the remainder are allhydrogen atoms; or in which R is a methyl group, R is a phenyl group andR R R and R are hydrogen atoms.

7. The compound of claim 1 which is l- (p-sulphamoylphenyl) -4-methy1-4-pheny l-pyrrolidin-2-one.

8. The compound of claim 1 which is 1-(2-chloro-4-sulphamoylphenyl)-4-phenyl-pyrrolidin-2-one.

9. The compound of claim 1 which is 1-(p-sulphamoylphenyl)-4-phenyl-pyrrolidin 2-one.

10. The compound of claim 1 which is 1-(2-fiuoro-4-sulphamoylphenyl)-4-phenyl-pyrrolidin-2-one.

References Cited UNITED STATES PATENTS 3,238,223 3/ 1966 Wilson et al.260-3265 JOSEPH A. NARCAVAGE, Primary Examiner US. Cl. X.R.

260326.5 SF, 326.5 FL; 424-228, 274

